This program project grant requests continuation of funding for the development of novel, non-addicting analgesics which cross the blood brain barrier. Our original goals remain unchanged. Our approach has been, and continues to be, emphasis on therapeutic applications of opioid delta (delta) receptor pharmacology. Progress has been rapid and rewarding. At the time of the original application, our understanding of opioid delta receptors and the therapeutic potential of compounds acting at these sites was limited to two concepts - (a) that compounds with selectivity for opioid delta receptors produced antinociception with reduced addiction liability, and (b) that compounds which acted at opioid delta receptors could positively or negatively modulate the antinociceptive actions of opioid mu (mu) agonists. During the initial funding period (i.e., approximately two years at the time of submission of this application) we have identified three potentially novel mechanisms of action for compounds with opioid delta receptor activity. Exploration of these mechanisms in addition to the concomitant evaluation of addiction liability and other side effects of the novel compounds which act by these mechanisms, is the main Specific Aim the aim of this application. These three novel mechanisms may offer significant opportunities for the development of therapeutic agents which will have limited, or no, physical dependence liability. First, we have demonstrated pharmacologically that subtypes of opioid delta receptors exist, and that these can be studied by novel agonists and antagonists. We have classified these opioid delta receptors as the delta1 receptor (DPDPE/DALCE-sensitive), and the delta2 receptor ([D-Ala2]deltorphin II/5'-NTII); the pharmacology of these delta receptor subtypes is one of the aims of this proposal. Second, a series of compounds with a novel, "self-potentiating" mechanism has been identified which may involve actions at a putative opioid mu-delta receptor complex; one of these peptides readily produces antinociception after i.p. administration and produces significantly lower levels of physical dependence when compared to morphine. Third, we have discovered a lead compound (SNF 9007) which shares high affinity at opioid delta receptors and at the CCKB receptor, offering an opportunity to explore the long- established link between opioid delta antinociception and the CCK system. with the continued discovery of novel compounds from the chemistry section of this project, each of these approaches will represent progress towards new modalities for pain relieving substances which will be clinically important.